Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers
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Kalliopi Tsafou1,7,*, Anna Maria Katschnig3,*, Branka Radic-Sarikas2,3,*, Cornelia Noëlle Mutz3, Kristiina Iljin5, Raphaela Schwentner3, Maximilian O. Kauer3, Karin Mühlbacher3, Dave N.T. Aryee3,4, David Westergaard1, Saija Haapa-Paananen5, Vidal Fey5, Giulio Superti-Furga2, Jeffrey Toretsky6, Søren Brunak1 and Heinrich Kovar3,4
1Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
3Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
4Department of Pediatrics, Medical University of Vienna, Vienna, Austria
5Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland
6Department of Oncology, Georgetown University, Medical Center, Washington, DC, USA
7Current address: Broad Institute of MIT and Harvard, Cambridge, MA, USA
*These authors contributed equally to this work
Heinrich Kovar, email: [email protected]
Keywords: high-throughput compound screening; Ewing sarcoma; drug-target network; apoptosis; BCL-2 inhibitors
Received: March 07, 2018 Accepted: June 22, 2018 Published: July 24, 2018
Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.
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